Genetic Study Suggests Pangolins May Possess an Evolutionary Advantage Against Coronaviruses

In most mammals, there are certain genes that can be likened to an "alarm system", informing an organism when foreign material such as a virus enters the body and triggering an immune response.

A new study published in the journal Frontiers in Immunology suggests that pangolins, despite being mammals, lack two of the genes involved in such an alarm system.

"Our work shows that pangolins have survived through millions of years of evolution without a type of antiviral defense that is used by all other mammals," Co-author Leopold Eckhart, PhD, from the Medical University of Vienna in Austria, says.

This research is timely as pangolins can be carriers of coronaviruses, yet they appear to be able to withstand the virus. If they lack the antiviral defense system used by all other mammals, what alternative protective mechanism is at play? According to Eckhart, this question warrants further investigation: "Further studies of pangolins will uncover how they manage to survive viral infections, and this might help to devise new treatment strategies for people with viral infections."

Technology Networks interviewed Eckhart to learn more about RNA sensor genes, the significance of the new research study and the challenges in this research field.

Molly Campbell (MC): You conducted a genomics analysis study of three species of pangolins. What are these species, and why did you choose them? How many species of pangolins exist?

Leopold Eckhart (LE): There are 8 species of pangolins and the genome sequences of three species have been determined and made publicly available. We investigated the species available: Malayan pangolin (Manis javanica), Chinese pangolin (Manis pentadactyla) and the tree pangolin (Manis tricuspis).

MC: For our readers that may be unfamiliar, please can you discuss what RNA sensor genes are?

LE: RNA viruses such as coronaviruses and influenza viruses depend on genetic information in the form of RNA. This viral RNA or RNA molecules that appear during viral replication are sensed by infected cells in humans and other mammals. Genes like IFIH1 and ZBP1 control the formation of particular RNA sensors.

MC: Please can you provide an overview of your experimental design?

LE: The SARS-CoV2 pandemic started by spill over of the virus to humans from another species. As pangolins were discussed as possible intermediate hosts of this virus, we investigated if something is special about the interaction of pangolins and viruses. We did not have access to pangolins but the complete genome information of three species of pangolins had been determined and made publicly available by other researchers. Our study was done by comparing gene sequences without any experiments on live animals.

MC: Your research found that IFIH1, a sensor of intracellular double-stranded RNA, has been inactivated by mutations in pangolins. Likewise, Z-DNA-binding protein (ZBP1), which senses both Z-DNA and Z-RNA, has been lost during the evolution of pangolins – please can you expand on the significance of these findings?

LE: IFIH1 and ZBP1 belong to an antiviral defense system that was previously considered essential for mammals. It is surprising that these genes have been lost during the evolution of any mammalian species. Survival of pangolins without IFIH1 and ZBP1 suggests that there are other mechanisms of antiviral defense.

MC: In the press release you say: "Our work shows that pangolins have survived through millions of years of evolution without a type of antiviral defense that is used by all other mammals" – meaning it's possible that they survive viral pathogens via an alternative mechanism. Although this wasn't explored in this study, do you have any hypotheses on this?

LE: Our data suggest that pangolins can either respond to RNA viruses through another sensor (for example, RIG-I) or that they tolerate infections. Tolerance would mean that the body allows the virus to grow to some extent without initiating an immediate and strong response that would potentially also damage its own tissues. It is possible that changes in the metabolism of infected animals reduce the growth of the virus but currently we do not know how pangolins control RNA virus infections.

MC: Why is advancing our understanding of the immune system mechanisms of pangolins relevant in regard to the current COVID-19 pandemic?

LE: Many severe cases of COVID-19 are characterized by an overreaction of the immune defense, known as a cytokine storm. A better understanding of the antiviral response of pangolins may help to find therapies that avoid inappropriate defense reactions in patients with COVID-19.

MC: What challenges exist in this field of research?

LE: If this research should be translated into new therapies, studies of live animals are necessary and only very few researchers are able to study exotic species such as pangolins. We do not know what the next emerging infectious disease will be – therefore, we should try to improve our understanding of the interactions of many different host species and their viruses and bacteria. We are doing basic research and we hope that support for comparative biology will increase.

Leopold Eckhart was speaking to Molly Campbell, Science Writer, Technology Networks.

Reference: Heinz Fischer, Erwin Tschachler and Leopold Eckhart. (2020). Pangolins lack IFIH1/MDA5, a cytoplasmic RNA sensor that initiates innate immune defense upon coronavirus infection. Frontiers in Immunology. DOI: 10.3389/fimmu.2020.00939.